G protein signal transduction pathways in the striatum play a pivotal role in the development of drug addiction. Many drugs of abuse including opioids and psychostimulants produce their effects by activating G proteins in the striatum, a major reward-processing nucleus in the brain. Our long term goal is to elucidate molecular and cellular mechanisms that regulate signaling in the striatal G protein pathways as a necessary prerequisite to understanding events that lead to substance dependence and designing strategies for the therapeutic correction. Increasing evidence suggests that Regulators of G protein Signaling (RGS) proteins play a crucial role in controlling G protein signaling pathways implicated in addiction. RGS proteins serve to curb G protein signaling and thus are optimally positioned to naturally counteract excessive activation of the G protein coupled receptors by drugs of abuse. Small molecule therapeutics targeting RGS proteins are emerging as promising therapeutic strategies. However, the mechanisms of RGS action in regulation of striatal G protein pathways are poorly understood. This proposal is focused on delineating the mechanisms by which key striatal RGS proteins: RGS9-2 and RGS7 regulate cellular signaling. Our recent findings indicate that the function of the two RGS proteins is closely intertwined. They exist as macromolecular complexes with several binding partners and undergo striking remodeling upon drug exposure as well as changes in neuronal excitability suggesting that plasticity in the RGS system contributes to molecular adaptations leading to addiction. Based on accumulated preliminary data we hypothesize that striatal RGS9-2 and RGS7 in cooperation with their binding partners differentially regulate G protein signaling from opioid and dopamine receptors to the central downstream effector adenylyl cyclase and that the plasticity in this system is a critical determinant of the addictive drug actions. This hypothesis will be tested by pursuing three complementary Specific Aims that seek to (1) to determine mechanisms of cAMP regulation by striatal RGS complexes, (2) understand receptor and G protein selectivity of their action and (3) test the role CaMKII? in regulating plasticity of striatal RGS complexes. The strategy proposed to address these Aims will entail a synergistic combination of genetic, behavioral, biochemical, and physiological approaches, exploiting the existence of a powerful array of reagents and animal models.